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Migraine and sleep disorders in children exhibit a bidirectional relationship. This relationship is based on shared pathophysiology. Migraine involves activation of the trigeminal vascular system. Nociceptive neurons that innervate the dura release various vasoactive peptides. Calcitonin gene-related peptide is the most active of these peptides. Neural pathways that are involved in sleep generation are divided into those responsible for circadian rhythm, wake promotion, non-rapid eye movement, and rapid eye movement sleep activation. Sleep state switches are a critical component of these systems. The cerebral structures, networks, and neurochemical systems that are involved in migraine align closely with those responsible for the regulation of sleep. Neurochemical systems that are involved with both the pathogenesis of migraine and regulation of sleep include adenosine, melatonin, orexin, and calcitonin gene-related peptide. Sleep disorders represent the most common comorbidity with migraine in childhood. The prevalence of parasomnias, obstructive sleep apnea, and sleep-related movement disorders is significantly greater in children migraineurs. Infantile colic is a precursor of childhood migraine. Treatment of comorbid sleep disorders is important for the appropriate management of children with migraine. Sleep-based behavioral interventions can be of substantial benefit. These interventions are particularly important in children due to limited evidence for effective migraine pharmacotherapy.
Learn More >Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic pain, some of which such as opioids have the risk of tolerance/dependence, overdose death with higher daily opioid doses for increasing analgesic effect. Opioid use disorders have already reached an epidemic level in the United States, therefore, non-opioid analgesic approach and/or use of non-pharmacologic interventions will be employed with increasing frequency. Viral vector mediated gene therapy is promising in clinical trials in the nervous system diseases. Glutamic acid decarboxylase (GAD) enzyme, a key enzyme in biosynthesis of GABA, plays an important role in analgesic mechanism. In the literature review, we used PubMed and BioRxiv to search the studies, and the eligible criteria include (1) manuscript written in English, (2) use of viral vectors expressing GAD67 or GAD65, and (3) preclinical pain models. We identified 13 eligible original research papers, in which the pain models include nerve injury, HIV-related pain, painful diabetic neuropathy, and formalin test. GAD expressed by the viral vectors from all of the reports produced antinociceptive effects. Restoring GABA systems is a promising therapeutic strategy for chronic pain, which provides evidence for the clinical trial of gene therapy for pain in the near future.
Learn More >Opioids have been used to treat pain and invoke pleasure for centuries. Modern scientific advancements have led to more potent, synthetic opioids. While certainly more effective in treating pain, they can also be much more addictive. Over the years the scientific community has developed a clearer understanding of the role opioid receptors play in causing and treating opioid use disorders (OUD) and we now know that OUD can develop in individuals taking opioids for "legitimate" pain. Current guidelines suggest that all prescribers (especially those prescribing opioids) be capable treating OUD. Pharmacological advances have led to a wide array of safe and effective treatment options to address OUDs. This paper will discuss the history of opioid development, what is known about the transition from analgesic uses to addiction and modern evidenced based treatment strategies to address OUDs.
Learn More >Chronic non-cancer pain (CNCP) among patients with substance use disorder (SUD) poses a risk for worse treatment outcomes. Understanding the association of CNCP with SUD is important for informing the need and potential benefits of pain assessment/management among those with SUDs.
Learn More >The role of immune mediators, including pro-inflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel up-regulated IL-20 via dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.
Learn More >A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, = 0.001) and gamma oscillatory activity ( = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load ( = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, < 0.001, adjusted -value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.
Learn More >To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain.
Learn More >Atopic dermatitis (AD), a chronic, highly pruritic skin disorder, impairs quality of life (QoL). Janus kinase inhibitors suppress inflammatory and pruritus-associated cytokine signaling in AD.
Learn More >Dipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole. These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue.
Learn More >Chronic non-cancer pain (CNCP) is a significant health burden among adults. Standard behavioral therapies typically focus on targeting negative affect (NA) and yield only modest treatment effects. The aims of this study were to systematically review and investigate the association between positive affect (PA) and pain severity among adults with CNCP. Databases search included MEDLINE (PubMed), PsycINFO, CINAHL, ProQuest Dissertations and Theses, OLASTER, Open Grey, and PsyArXiv (inception to July 23, 2019). We analyzed studies that: (1) employed observational, experimental, or intervention study designs; (2) enrolled individuals with CNCP (pain ≥ 12 weeks); and (3) reported full quantitative results on outcomes. Two researchers independently screened articles, extracted data, and assessed the risk of bias. The main meta-analysis was followed by subgroup analyses. All analyses were performed using random-effects models. Formal tests for heterogeneity (Q-statistic; I) and publication bias (p-curve and p-uniform*) were performed. We meta-analyzed 29 studies with 3521 participants. Results demonstrated that PA inversely impacts pain severity in people with CNCP (r = -0.23). Subgroup analyses showed a significant effect for gender and marginally significant effects for age in studies that adjusted for NA. On average, effect sizes for observational studies were larger in studies with a higher proportion of female respondents and in studies that did not adjust for NA. Finally, larger effect sizes were found in intervention studies with older compared with younger samples.
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